Experiments were continued examining the interaction of complement with Trypanosoma cruzi and Leishmania major, in an effort to elucidate the mechanism of parasite preadaptation to complement resistance, and to define the parasite and host molecules involved in invasion of host cells. We identified molecules produced by metacyclic and tissue culture trypomastigotes of T. cruzi which inhibit the formation and accelerate the intrinsic decay of complement C3 convertases and hence explain the developmentally regulated resistance of these forms to complement-mediated lysis. These molecules, which are protease sensitive and retained on Concavalin A. sepharose, were purified by FPLC anion exchange and chromatofocusing from 35S-labeled parasites, and migrated as a 87-93 kd band by SDS-PAGE. In separate studies, we have shown that C1q enhances infection of macrophages by trypomastigotes. The deposition of complement on infective and non-infective promastigotes of Leishmania major was compared. Nearly equivalent amounts of C3 were deposited on non-infective, serum sensitive, log phase parasites and on a subset of peanut-non- agglutinable (PNA-), serum resistant, stationary phase parasites. Almost 85% of C3 on both log and PNA- was present as C3b, which was attacted to the developmentally regulated glycolipid, excreted factor a critical component for parasite infectivity. The mechanism of serum resistance in PNA- was different from that in T. cruzi trypomastigotes since in L. major, a C5b-9 complex formed but was released from the parasite surface without causing a lethal event. The attachment and entry of parasites into human mononuclear cells and mouse macrophages was inhibited by monoclonal antibodies to the C3b receptor, CR1. Complement deposition on serum resistant tachyzoites of Toxoplasma gondii was tested. The form of C3 on the parasite surface and tachyzoite molecules binding C3 were determined, as a prelude to examining the role of C3 fragments and antibody in cell invasion by T. gondii.